Postnatal developmental programmed cell death in dopamine neurons

Abstract

The prenatal development of dopamine (DA) neurons of the substantia nigra (SN) is characterized by their birth, specification, and migration to their final positions. Their postnatal development is characterized by the establishment of contact and interactions between the SN and other neural nuclei, particularly the striatal target, by extension of axons, terminal differentiation, and synapse formation. In this postnatal context there is a natural cell death event, which is apoptotic in nature and biphasic in time course, with an initial peak on postnatal day (PND) 2, and a second on PND14. By PND20 the event has largely subsided. This natural cell death event is regulated in vivo by interaction with striatal target: it is augmented by axon-sparing target lesion, DA terminal destruction, and medial forebrain bundle axotomy. This target dependence is present largely within only the first two postnatal weeks. The striatal target-derived neurotrophic factor(s) that regulate this death event are unknown. We have shown, in a postnatal primary culture model of mesencephalic DA neurons, that glia-derived neurotrophic factor (GDNF) is unique in its ability to support their viability by suppressing apoptosis. We have also recently found that intrastriatal injection of GDNF in vivo suppresses apoptosis, and injection of neutralizing antibodies augments it. Thus, GDNF is a leading candidate for a striatum-derived neurotrophic factor for DA neurons during development.